SAR Studies of Exosite-Binding Substrate-Selective Inhibitors of ADisintegrin And Metalloprotease 17 (ADAM17) and Application as Selective in Vitro Probes
Document Type
Article
Publication Date
2015
Digital Object Identifier (DOI)
https://doi.org/10.1021/acs.jmedchem.5b00354
Abstract
ADAM17 is implicated in several debilitating diseases. However, drug discovery efforts targeting ADAM17 have failed due to the utilization of zinc-binding inhibitors. We previously reported discovery of highly selective nonzinc-binding exosite-targeting inhibitors of ADAM17 that exhibited not only enzyme isoform selectivity but synthetic substrate selectivity as well ( J. Biol. Chem. 2013, 288, 22871). As a result of SAR studies presented herein, we obtained several highly selective ADAM17 inhibitors, six of which were further characterized in biochemical and cell-based assays. Lead compounds exhibited low cellular toxicity and high potency and selectivity for ADAM17. In addition, several of the leads inhibited ADAM17 in a substrate-selective manner, which has not been previously documented for inhibitors of the ADAM family. These findings suggest that targeting exosites of ADAM17 can be used to obtain highly desirable substrate-selective inhibitors. Additionally, current inhibitors can be used as probes of biological activity of ADAM17 in various in vitro and, potentially, in vivo systems.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Journal of Medicinal Chemistry, v. 58, issue 15, p. 5808-5824
Scholar Commons Citation
Knapinska, Anna M.; Dreymuller, Daniela; Ludwig, Andreas; Smith, Lyndsay; Golubkov, Vladislav; Sohail, Anjum; Fridman, Rafael; Giulianotti, Marc; LaVoi, Travis M.; Houghten, Richard A.; Fields, Gregg B.; and Minond, Dmitriy, "SAR Studies of Exosite-Binding Substrate-Selective Inhibitors of ADisintegrin And Metalloprotease 17 (ADAM17) and Application as Selective in Vitro Probes" (2015). Chemistry Faculty Publications. 192.
https://digitalcommons.usf.edu/chm_facpub/192
